Abstract
Overexpression of plasminogen activator inhibitor 1 (PAI-1) reduces tumor cell migration in vitro and metastasis in mice in vivo by mechanisms involving either inhibition of urokinase plasminogen activator (u-PA) activity or competition for an integrin binding site on vitronectin. To analyze the effects of PAI-1 on tumor cell migration in vitro and metastasis in vivo, recombinant adenoviral vectors expressing wild-type or mutant PAI-1 proteins were constructed. The mutant PAI-1 proteins were defective in either vitronectin binding (PAI-1VN-), plasminogen activator inhibition (PAI-1INH-) or both (PAI-1VN-,INH-). In vitro, migration of HT1080 human fibrosarcoma cells through a reconstituted extracellular matrix (ECM) was reduced 73% by overexpression of wild-type PAI-1 and 65% by PAI-1VN- compared with control virus-infected cells. Migration of cells infected by virus expressing either PAI-1INH- or PAI-1VN-,INH- was unaffected, indicating a requirement for plasminogen activator inhibitory activity. In vivo, however, only overexpression of wild-type PAI-1 reduced the burden of metastasis by 68% compared with the control group. This indicates that both u-PA inhibition and PAI-1 ECM interactions contribute to the mechanism of PAI-1-mediated regulation of cell migration.
Original language | English (US) |
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Pages (from-to) | 584-591 |
Number of pages | 8 |
Journal | International Journal of Cancer |
Volume | 102 |
Issue number | 6 |
DOIs | |
State | Published - Dec 20 2002 |
Keywords
- Adenovirus
- Cell movement
- Gene transfer
- Neoplasm metastasis
- Plasminogen activator inhibitor 1
- Vitronectin
ASJC Scopus subject areas
- Oncology
- Cancer Research